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- Title
Prolonged mechanical unloading affects cardiomyocyte excitation-contraction coupling, transverse-tubule structure, and the cell surface.
- Authors
Ibrahim, Michael; Masri, Abeer Al; Navaratnarajah, Manoraj; Siedlecka, Urszula; Soppa, Gopal K.; Moshkov, Alexey; Al-Saud, Sara Abou; Gorelik, Julia; Yacoub, Magdi H.; Terracciano, Cesare M. N.
- Abstract
Prolonged mechanical unloading (UN) of the heart is associated with detrimental changes to the structure and function of cardiomyocytes. The mechanisms underlying these changes are unknown. In this study, we report the influence of UN on excitation contraction coupling, Ca2+-induced Ca2+ release (CICR) in particular, and transverse (t)-tubule structure. UN was induced in male Lewis rat hearts by heterotopic abdominal heart transplantation. Left ventricular cardiomyocytes were isolated from the transplanted hearts after 4 wk and studied using whole-cell patch clamping, confocal microscopy, and scanning ion conductance microscopy (SICM). Recipient hearts were used as control (C). UN reduced the volume of cardiomyocytes by 56.5% compared with C (UN, n=90; C, n=59; P<0.001). The variance of time-to-peak of the Ca2+ transients was significantly increased in un-loaded cardiomyocytes (UN 227.4±24.9 ms², n=42 vs. C 157.8±18.0 ms², n=40; P<0.05). UN did not alter the action potential morphology or whole-cell L-type Ca2+ current compared with C, but caused a significantly higher Ca2+ spark frequency (UN 3.718±0.85 events/ 100µm/s, n=47 vs. C 0.908±0.186 events/100µm/s, n=45; P<0.05). Confocal studies showed irregular distribution of the t tubules (power of the normal t-tubule frequency: UN 8.13±1.1210 , n=57 vs. C 20.60± 3.174 x 105, n=56; P<0.001) and SICM studies revealed a profound disruption to the openings of the t tubules and the cell surface in unloaded cardiomyocytes. We show that UN leads to a functional uncoupling of the CICR process and identify disruption of the t-tubule-sarcoplasmic reticulum interaction as a possible mechanism.
- Subjects
HEART cells; CONFOCAL microscopy; HEART transplantation; SARCOPLASMIC reticulum; CELL membranes
- Publication
FASEB Journal, 2010, Vol 24, Issue 9, p3321
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-156638